What are the causes of elevated Alanine Transaminase (ALT) levels?

Causes of Elevated ALT

Elevated ALT levels result from hepatocellular injury, with nonalcoholic fatty liver disease (NAFLD) being the most common cause in developed countries, followed by alcohol-induced liver disease, viral hepatitis, and drug-induced liver injury. 1, 2

Primary Hepatic Causes

Most Common Etiologies

• Nonalcoholic fatty liver disease (NAFLD) accounts for the majority of isolated ALT elevations, with prevalence of 20-30% in the general population, increasing to 70% in obesity and 90% in diabetes mellitus 2

• NAFLD typically presents with an AST:ALT ratio <1, distinguishing it from alcoholic liver disease 1, 2

• The spectrum ranges from simple steatosis (70-75% of cases) to nonalcoholic steatohepatitis (NASH) with inflammation (25-30% of cases) 2

• Alcohol-induced liver disease presents with ALT elevation, characteristically with an AST:ALT ratio >2 2

• Even moderate alcohol consumption can significantly impact liver enzyme levels and impede recovery 1

• Viral hepatitis (acute and chronic hepatitis B, C, and E) commonly causes ALT elevation 1, 2

• ALT elevation in chronic hepatitis B may fluctuate, particularly during immune clearance or reactivation phases 3

• Screening for viral hepatitis is essential in unexplained ALT elevation 2

• Drug-induced liver injury (DILI) is a frequent cause, accounting for approximately 11% of notably elevated ALT cases 2, 4

• Common culprits include statins, antibiotics, antiepileptics, herbal supplements, and over-the-counter medications 1, 2

• Immune checkpoint inhibitors can cause immune-mediated liver injury with isolated ALT elevation 3, 2

Biliary and Vascular Causes

• Choledocholithiasis is the most common cause of notably high ALT (>500 U/L), accounting for 34% of cases 4
• Ischemic hepatitis accounts for 18% of notably elevated ALT cases, with approximately 35% liver-related mortality 4
• Hepatic vein thrombosis and congestive heart failure can cause ALT elevation 3

Less Common Hepatic Causes

• Autoimmune hepatitis can present with isolated ALT elevation 2

• Note that anti-nuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA) may be positive in low titers in NASH patients, complicating differentiation from autoimmune hepatitis 2

• Hereditary hemochromatosis should be considered in persistent unexplained ALT elevation 2

• Alpha1-antitrypsin deficiency is a rare cause 2

• Wilson disease should be considered particularly in younger patients with unexplained ALT elevation 2

Non-Hepatic Causes

• Muscle injury from intensive exercise, particularly weight lifting, can elevate ALT 2

• Statin-related muscle injury can cause elevated ALT and AST 2

• Testing for creatine phosphokinase (CK), aldolase, or other muscle-related enzymes confirms non-hepatic origin 2

• Cardiac conditions including acute myocardial infarction can elevate AST more than ALT 5

• Hypothyroidism can cause transaminase elevations 1, 5

• Polymyositis and acute muscle injury are additional non-hepatic causes 5

Metabolic and Systemic Factors

• Obesity is associated with ALT elevation in 30.2% of cases, with significant positive correlation between ALT levels and body mass index 6, 7
• Metabolic syndrome components including diabetes and hypertension are risk factors for NAFLD-related ALT elevation 1
• ALT activity may be affected by gender, abnormal lipid and carbohydrate metabolism, fatty liver, and uremia 3, 2

Important Clinical Considerations

• Gender-specific reference ranges: Normal ALT levels are 29-33 IU/L for men and 19-25 IU/L for women, significantly lower than traditional laboratory reference ranges 1, 2
• Severity classification: Mild (<5× ULN), moderate (5-10× ULN), or severe (>10× ULN) 1, 2
• ALT specificity: ALT is highly specific for liver injury due to its primary concentration in hepatocytes with minimal presence in other tissues 1

Common Pitfalls

• Relying solely on ALT levels can be misleading, as there isn't always strict correlation between the extent of liver cell necrosis and the degree of ALT elevation 3, 2
• Mild asymptomatic increases in ALT (<3× ULN) without elevated bilirubin are often non-specific and may be related to NAFLD, dietary changes, or vigorous exercise 2
• In chronic viral hepatitis, the elevation of liver enzyme may not correlate well with the degree of liver damage 5
• AST is less specific for liver injury and can be elevated in cardiac, skeletal muscle, kidney, and red blood cell disorders 1